Microwave-mediated regioselective synthesis of novelpyrimido[1,2-a]pyrimidines under solvent-free conditions

Jean Jacques Vanden Eynde,a,p Nancy Hecq,a Olga Kataevab and C. Oliver Kappec

aDepartment of Organic Chemistry, University of Mons-Hainaut, Place du Parc 20, B-7000 Mons, BelgiumbA.E. Arbuzov Institute of Organic and Physical Chemistry, Russian Academy of Sciences, A.E. Arbuzov Street 8,

Kazan 420083, Russian FederationcInstitute of Chemistry, Karl-Franzens-University Graz, Heinrichstrasse 28, A-8010 Graz, Austria

Received 9 October 2000; accepted 11 December 2000

AbstractÐEthyl 2-amino-4-aryl-1,4-dihydro-6-phenylpyrimidine-5-carboxylates readily react, under microwave irradiation and solvent-free conditions, with 3-formylchromone or diethyl (ethoxymethylene)malonate to yield novel pyrimido[1,2-a]pyrimidines. The structure ofthe ®nal products, deduced from the spectral data and con®rmed by X-ray analysis, allows us to suggest reaction pathways. q 2001 ElsevierScience Ltd. All rights reserved.

1. Introduction

In recent years, there has been increasing interest in thedesign of alkyl 1,4-dihydropyrimidine-5-carboxylates (1,4-DHPMs) and related Biginelli-like compounds1 which arepresented as valuable substitutes2 for the well-knownNifedipinew and other 1,4-dihydropyridine drugs,3

clinically used in the treatment of cardiovascular diseases.This interest is illustrated, i.e. by the disclosure of elegantprotocols involving solid phase synthesis approaches4 aswell as (solvent-free) preparations under microwaveirradiation.5

The purpose of the present work is to extend the scope ofthose studies to 2-amino derivatives, and especially to theevaluation of their synthetic potential for the construction ofnovel pyrimido[1,2-a]pyrimidines, a ring system that canbe found in marine-derived natural products such ascrambescidin6 and batzelladine7 alkaloids.

2. Results and discussion

2.1. Preparation of the starting 2-amino-1,4-DHPMs2a±e

A recent paper of Milcent8 describes the synthesis (Scheme1) of ethyl 2-amino-4-aryl-1,4-dihydro-6-phenylpyrimi-dine-5-carboxylates (2) from ethyl 3-aryl-2-benzoyl-

propenoates (1) and guanidine in DMF in the presence ofan inorganic base (sodium hydrogen carbonate). This pro-cedure affords the desired heterocycles within reactiontimes ranging from 8 to 48 h, but reported yields (notoptimized) do not exceed 40% because of a competitivereaction yielding diethyl 2,4,6,8-tetraryl-4,6-dihydro-1H-pyrimido[1,2-a]pyrimidine-3,7-dicarboxylates (3). As thesebicyclic derivatives arise from Michael-type condensationsbetween two molecules of ester (1) and guanidine,8 wereasoned that their formation could perhaps be disfavoredwhen starting directly from arylaldehydes, ethyl benzoyl-acetate, and guanidine. This proposal is veri®ed as thethree-component reactions enabled us to obtain derivatives2a±e within 3 h in 75±90% yields whereas formation of 3was not detected.

2.2. Reactions between the 2-amino-1,4-DHPMs 2a±eand 3-formylchromone 4

Diamines are known to react with 3-formylchromone 4 toyield pyrimidines.9 The reaction initially takes place on theformyl group and is followed by an intramolecular attack ofthe second amine function on the C-2 atom of the pyronering followed by the opening of that ring (Scheme 2). Insuch a sequence, derivatives 2 are excellent candidates forthe preparation of bicyclic systems but, due to the presenceof three nitrogen atoms in 2, formation of two isomericsubstances (4-aryl (5) or 2-aryl (6) derivatives) may beforeseen as illustrated in Scheme 2.

Experimentally we observed (NMR) that only one series ofisomers (5 (2H), see Scheme 2) was obtained when thereactants are heated in boiling ethanol for several hours.However, we felt unsatis®ed with those experimental

Tetrahedron 57 (2001) 1785±1791Pergamon

TETRAHEDRON

0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.PII: S0040-4020(00)01157-1

Keywords: Biginelli compounds; pyrimidine; microwave; solvent-freeconditions.p Corresponding author. Tel.: 132-65-373338; fax: 132-65-373054;

e-mail: jjvde@umh.ac.be

J. J. Vanden Eynde et al. / Tetrahedron 57 (2001) 1785±17911786

Scheme 1. Preparation of compounds 2a±e and 3.

Scheme 2. Reactions between 2-amino-1,4-DHPMs (2) and 3-formylchromone (4).

J. J. Vanden Eynde et al. / Tetrahedron 57 (2001) 1785±1791 1787

conditions, and we decided to perform the reactions undermicrowave irradiation.10 In that way, we isolated the same®nal products but advantageously in better yields, undersolvent-free conditions, and within a few minutes.

In the 1H NMR spectra (Fig. 1) of the ®nal products, thereare three signals (singlet) between 5.0 and 6.5 ppm. The lessdeshielded signal in this range is located at 5.4 ppm: this is atypical value for 1H chemical shifts observed in the NMR

spectra of Biginelli-like 1,4-DHPMs and it allows toattribute the signal to a proton on a sp3 carbon atom bearinga (hetero)aryl group. As this position is constant whichever,that (hetero)aryl substituent is, structures 5 (2H) or 6 (4H)can be suggested (indeed, as illustrated by the valuescollected in Table 1, the chemical shift of a Ar±CH protonis highly dependent11 on the nature of the aromatic group:such a dependence is also observed in the spectra of thestarting heterocycles (2). The second signal (H on a sp2

Figure 1. 1H NMR spectrum of compound 5b.

Scheme 3. Reactions between 2-amino-1,4-DHPMs (2) and diethyl (ethoxymethylene)malonate (7).

Table 1. 1H chemical shifts of CH3 protons in various Ar±CH3 compounds

Ar in Ar±CH3 C6H5 4-(CH3)±C6H4 4-(OCH3)±C6H4 4-Cl±C6H4 2-thienyl

d CH3 2.40 2.30 2.25 2.35 2.55

J. J. Vanden Eynde et al. / Tetrahedron 57 (2001) 1785±17911788

carbon atom) appears around 5.9 ppm when the substituenton the system is a phenyl ring or a substituted phenyl ring,and is shifted down®eld to 6.2 ppm when the substituent is athienyl group. The signal is therefore attributed to the H(6)proton; the signal due to the H(8) proton is located at6.0 ppm and its position does not vary with the nature ofthe (hetero)aryl substituent on the system. Those data areconsistent with structures 5 (2H) only.

2.3. Reactions between the 2-amino-1,4-DHPMs 2a±eand diethyl (ethoxymethylene)malonate 7

The situation is more complex when derivatives 2 areallowed to react with diethyl (ethoxymethylene)malonate(7). Indeed, four series of isomeric pyrimido[1,2-a]pyrimi-dines can be formed (Scheme 3). Once again, when thereactions are conducted in boiling ethanol, or under micro-wave irradiation, only one series of compounds is obtained.In the 1H NMR spectra, there is no signal between 5.0 and6.0 ppm. Therefore, the signal due to the proton on the sp3

carbon atom of the heterocyclic system is highly deshieldedwhen compared with the chemical shifts observed for thestarting heterocycles 2 (d C(4)± H in 2: between 5.2 and5.6 ppm). Such a deshielding can be explained by thein¯uence of the carbonyl moiety when it is in close vicinityof the considered proton, and is therefore indicating a 6-oxostructure 8 or 10.

As the chemical shift of this proton varies when going from

an aryl substituent (compounds a±d) to a thienyl substituent(compound e), the bicyclic derivatives should belong toseries 8. This conclusion is con®rmed by the structure(Fig. 2) obtained from the X-ray analysis of the product,formed by the interaction between 2c and 7. According tothe X-ray single crystal diffraction study, the pyrimidinonecycle is planar, the exocyclic ester group being twisted fromthis plane by 26(2)8. The other unsaturated 6-membered ringadopts an asymmetric boat conformation with a planarC2C3N10C9 fragment, the pseudoaxial benzene ringC20±C25 being perpendicular to this fragment. The phenylsubstituent attached to C2 is twisted around the C2±C11bond by 74(2)8 to avoid steric interactions with the neigh-bouring ethoxycarbonyl substituent at C3. In the crystal,molecules 8c form centrosymmetric dimers via inter-molecular hydrogen bonds: N8±H8´ ´ ´N1 [12x, 12y,12z], N8±H8 0.99(4), H8´ ´ ´N1 1.97(5) AÊ , /N8±H8´ ´ ´N11708.

2.4. Reaction pathways

We have not been able to isolate the uncyclized inter-mediates, neither by reducing microwave irradiationtimes, nor by performing the syntheses in a solvent at re¯uxor at room temperature. Anyway, the structure of the ®nalproducts 5 indicates that they result from the nucleophilicattack of the exocyclic nitrogen atom of 2 on the formylfunction of 4 and that the ring closure involves theN(3) nitrogen atom of the pyrimidine cycle. This situation

Figure 2. Solid state structure of compound 8c.

J. J. Vanden Eynde et al. / Tetrahedron 57 (2001) 1785±1791 1789

parallels previous results, demonstrating a greater suscepti-bility of the N(3) atom towards electrophiles, whencompared to the N(1) atom.1a Similarly, reactions performedfrom diethyl (ethoxymethylene)malonate involve the sameexocyclic and N(3) nitrogen atoms of the starting hetero-cycles 2.

3. Conclusion

In this work, we demonstrated that ethyl 2-amino-4-aryl-1,4-dihydro-6-phenylpyrimidine-5-carboxylates (2) regio-selectively react with 3-formylchromone (4) or diethyl(ethoxymethylene)malonate (7) to afford pyrimido[1,2-a]pyrimidines (5 and 8, respectively) which had not beendescribed previously. Interestingly, we observed that thesebicyclic derivatives can be prepared advantageously in amicrowave oven and in the absence of organic solvent,thus contributing to the promotion of economical andenvironmentally friendly experimental procedures.

4. Experimental

4.1. General

1H and 13C NMR spectra were obtained using a Jeol JNP-PM X60 spectrometer (60 MHz for 1H at 1.4 T) and aBruker AMX-300 spectrometer (300 MHz for 1H and75 MHz for 13C at 7 T); chemical shifts (d) are given inppm using TMS as internal reference. IR spectra wererecorded on a Perkin±Elmer FTIR 1760 K spectro-photometer. Melting points (not corrected) were determinedon an electrothermal 9100 apparatus. Solvents are com-mercially available (Aldrich Co., Acros Organics) andwere used without further puri®cation. The elementalanalyses were carried out at the Station de Haute Belgique(Libramont-Chevigny, Belgium). Crystallographic data(excluding structure factors) of 7c have been deposited atthe Cambridge Crystallographic Data Centre as supple-mentary publication no. CCDC 149469. Copies of the dataare available without charge from: The Director, CCDC, 12Union Road, Cambridge CB2 1EZ, UK (Fax: 14412-23336033; e-mail: deposit@ccdc.cam.ac.uk).

4.2. X-Ray structure determination

X-Ray data for crystals 8c were collected on a CAD4 Enraf-Nonius automatic diffractometer with graphite mono-chromated lMoKa radiation using v /2u -scan mode in therange 28<u<278 at 208C. The stability of the crystal andthat of the experimental conditions were checked every 2 husing three control re¯ections, while the orientation wasmonitored every 200 re¯ections by centering threestandards. Neither decay, nor absorption correction (m Mo0.87 cm21) was necessary. Corrections for Lorentz andpolarization effects were applied.

Crystals 8c, C26H25O6N3 (colorless, needles,0.4£0.1£0.1 mm3), M 475.51, F(000) 500, triclinic.Twenty-®ve centered re¯ections were used to determineunit cell dimensions: a 7.147(3) AÊ , b 11.969(3) AÊ , c14.874(6) AÊ , a 75.93(2)8, b 81.98(2)8, g 81.95(2)8, V

1214.7(8) AÊ 3, dcalcd 1.30 g/cm3, Z 2, space group P1bar. Atotal of 5342 re¯ections were measured, of which only 992were with I . 3s.

The phase problem was solved by direct methods using theprogram sir.12 The structure was developed by difference-Fourier calculations interspersed with cycles of full-matrixleast-squares re®nements. All non-hydrogen atoms werere®ned anisotropically, and hydrogen atoms were locatedfrom difference-Fourier maps and added to structure factorcalculations with ®xed positional and thermal parameters.The ®nal agreement factors are R 0.088, Rw 0.099. All calcu-lations were carried out using the MolEn package.13

4.3. Synthesis

4.3.1. Preparation of the starting 2-amino-1,4-DHPMs2a±e. A mixture of aldehyde (20 mmol), ethyl benzoyl-acetate (4.2 g, 3.8 mL, 22 mmol), guanidine hydrochloride(2.3 g, 24 mmol), and sodium hydrogen carbonate (6.7 g,80 mmol) in DMF (40 mL) was stirred at 708C for 3 h.After cooling, the mixture was poured onto crushed ice.The precipitate was ®ltered and thoroughly washed withwater. Compounds (Yield) 2a (75%), 2b (85%), 2c (75%),and 2d (85%) have been described in the literature.8

4.3.2. Ethyl 2-amino-1,4-dihydro-6-phenyl-4-(2-thienyl)-pyrimidine-5-carboxylate 2e. Yield: 85%. Mp (EtOH):223±2258C. IR (KBr): 3395, 3357, 1673 cm21. 1H NMR(DMSO): 0.7 (t, 3H, J�7 Hz, CH3), 3.8 (q, 2H, J�7 Hz,CH2), 5.6 (s, 1H, H(4)), 6.7±7.5 (m, 10H, Ph, thienyl, andNH2).

13C NMR (DMSO): 13.6, 47.4, 53.2, 58.2, 98.1,123.1, 124.5, 126.5, 126.8, 127.2, 128.1, 150.4, 155.1,160.0, 165.6. Anal. Calcd for C17H17N3O2S (327.40):C, 62.37; H, 5.23; N, 12.84. Found: C, 62.27; H, 4.88; N,12.65.

4.3.3. Reactions between the 2-amino-1,4-DHPMs 2a±eand 3-formylchromone 4 in ethanol. A mixture of ethyl2-amino-4-aryl-1,4-dihydro-6-phenylpyrimidine-5-carboxyl-ate 2 (1.5 mmol) and 3-formylchromone 4 (0.27 g,1.5 mmol) in ethanol was heated under re¯ux for 4 h.After cooling, the precipitate was ®ltered and recrystallized.Compounds (Yield): 5a (70%), 5b (80%), 5c (80%), 5d(80%), 5e (60%).

4.3.4. Reactions between the 2-amino-1,4-DHPMs 2a±eand 3-formylchromone 4 under microwave irradiation.A mixture of ethyl 2-amino-4-aryl-1,4-dihydro-6-phenyl-pyrimidine-5-carboxylate 2 (1.5 mmol) and 3-formyl-chromone 4 (0.27 g, 1.5 mmol) was irradiated for 20 minin a domestic microwave oven (Whirlpool AKL260,400 W). The solid was recrystallized. Yields exceed 95%.

4.3.5. Ethyl 7-(2-hydroxybenzoyl)-2,4-diphenyl-2H-pyrimido[1,2-a]pyrimidine-3-carboxylate 5a. Mp(EtOH): 225±2268C. IR (KBr): 3500±2500, 1697,1666 cm21. 1H NMR (CDCl3): 0.7 (t, 3H, J�7 Hz, CH3),3.9 (q, 2H, J�7 Hz, CH2), 5.4 (s, 1H, H(2)), 5.9 (s, 1H,H(6)), 6.0 (s, 1H, H(8)), 7.0±8.0 (m, 15H, Ar, and OH).13C NMR (CDCl3): 13.5, 57.4, 60.2, 82.9, 103.3, 108.6,119.2, 122.3, 124.1, 127.4, 127.6, 128.3, 128.5, 129.2,130.2, 135.0, 135.7, 139.5, 140.2, 141.4, 146.9, 149.1,

J. J. Vanden Eynde et al. / Tetrahedron 57 (2001) 1785±17911790

155.9, 164.8, 179.6. Anal. Calcd for C29H23N3O4 (477.52):C, 72.94; H, 4.86; N, 8.80. Found: C, 72.63; H, 4.85; N,8.35.

4.3.6. Ethyl 7-(2-hydroxybenzoyl)-4-(4-methylphenyl)-2-phenyl-2H-pyrimido[1,2-a]pyrimidine-3-carboxylate 5b.Mp (EtOH): 223±2248C. IR (KBr): 3500±2500, 1687,1669 cm21. 1H NMR (CDCl3): 0.8 (t, 3H, J�7 Hz, CH3),2.3 (s, 3H, ArCH3), 3.8 (q, 2H, J�7 Hz, CH2), 5.4 (s, 1H,H(2)), 5.9 (s, 1H, H(6)), 6.0 (s, 1H, H(8)), 7.0±8.0 (m, 14H,Ar, and OH). 13C NMR (CDCl3): 14.0, 21.8, 57.7, 60.7,83.4, 104.0, 109.2, 118.6, 123.1, 124.7, 127.9, 128.2,128.8, 129.1, 130.4, 130.7, 135.6, 136.3, 137.1, 139.7,141.6, 147.1, 149.6, 156.5, 165.4, 180.2. Anal. Calcd forC30H25N3O4 (491.54): C, 73.31; H, 5.13; N, 8.55. Found:C, 73.26; H, 5.36; N, 8.88.

4.3.7. Ethyl 7-(2-hydroxybenzoyl)-4-(4-methoxyphenyl)-2-phenyl-2H-pyrimido[1,2-a]pyrimidine-3-carboxylate5c. Mp (EtOH): 222±2248C. IR (KBr): 3500±2500, 1689,1665 cm21. 1H NMR (CDCl3): 0.8 (t, 3H, J�7 Hz, CH3), 3.8(s, 3H, OCH3), 3.9 (q, 2H, J�7 Hz, CH2), 5.4 (s, 1H, H(2)),5.8 (s, 1H, H(6)), 6.0 (s, 1H, H(8)), 6.8±8.0 (m, 14H, Ar, andOH). 13C NMR (CDCl3): 13.4, 55.3, 56.9, 60.6, 84.2, 103.5,108.5, 114.5, 117.2, 123.0, 124.1, 127.4, 128.2, 128.4,128.7, 128.9, 130.1, 131.5, 135.0, 135.7, 146.0, 148.9,155.8, 160.2, 164.9, 179.6. Anal. Calcd for C30H25N3O5

(507.55): C, 71.00; H, 4.97; N, 8.28. Found: C, 70.67; H,5.08; N, 7.98.

4.3.8. Ethyl 4-(4-chlorophenyl)-7-(2-hydroxybenzoyl)-2-phenyl-2H-pyrimido[1,2-a]pyrimidine-3-carboxylate 5d.Mp (EtOH): 228±2298C. IR (KBr): 3500±2500, 1685,1669 cm21. 1H NMR (CDCl3): 0.8 (t, 3H, J�7 Hz, CH3),3.9 (q, 2H, J�7 Hz, CH2), 5.4 (s, 1H, H(2)), 5.9 (s, 1H,H(6)), 6.0 (s, 1H, H(8)), 7.0±8.0 (m, 14H, Ar, and OH).13C NMR (CDCl3): 13.4, 56.7, 60.3, 82.7, 103.0, 108.6,117.9, 122.6, 123.9, 127.4, 128.1, 128.5, 128.9, 129.4,130.2, 135.0, 135.1, 135.8, 137.9, 140.0, 147.2, 148.7,155.8, 164.7, 179.4. Anal. Calcd for C29H22ClN3O4

(511.97): C, 68.04; H, 4.33; N, 8.21. Found: C, 67.95; H,4.54; N, 8.29.

4.3.9. Ethyl 7-(2-hydroxybenzoyl)-2-phenyl-4-thienyl-2H-pyrimido[1,2-a]pyrimidine-3-carboxylate 5e. Mp(EtOH): 254±2578C. IR (KBr): 3500±2500, 1696,1666 cm21. 1H NMR (CDCl3): 0.8 (t, 3H, J�7 Hz, CH3),3.9 (q, 2H, J�7 Hz, CH2), 5.4 (s, 1H, H(2)), 6.0 (s, 1H,H(8)), 6.2 (s, 1H, H(6)), 6.9±7.9 (m, 13H, Ar, thienyl, andOH). 13C NMR (CDCl3): 13.5, 52.8, 60.3, 82.8, 103.4,108.7, 118.1, 122.6, 124.0, 126.6, 126.7, 126.9, 127.4,128.2, 128.5, 130.2, 135.1, 135.7, 140.0, 142.1, 147.5,148.6, 155.9, 164.6, 179.4. Anal. Calcd for C27H21N3O4S(483.54): C, 67.07; H, 4.38; N, 8.69. Found: C, 67.19; H,4.02; N, 8.67.

4.3.10. Reactions between the 2-amino-1,4-DHPMs 2a±eand diethyl (ethoxymethylene)malonate 7 in ethanol. Amixture of ethyl 2-amino-4-aryl-1,4-dihydro-6-phenyl-pyrimidine-5-carboxylate 2 (1.5 mmol) and diethyl (ethoxy-methylene)malonate 7 (0.32 g, 0.30 mL, 1.5 mmol) inethanol (10 mL) was heated under re¯ux for 8 h. Afterevaporation of the solvent, the residue was recrystallized.

Compounds (Yield): 8a (50%), 8b (50%), 8c (45%), 8d(60%), 8e (40%).

4.3.11. Reactions between the 2-amino-1,4-DHPMs 2a±eand diethyl (ethoxymethylene)malonate 7 under micro-wave irradiation. A mixture of ethyl 2-amino-4-aryl-1,4-dihydro-6-phenylpyrimidine-5-carboxylate 2 (1.5 mmol)and diethyl (ethoxymethylene)malonate 7 (0.32 g,0.30 mL, 1.5 mmol) was irradiated for 10 min in a domesticmicrowave oven (Whirlpool AKL260, 400 W). The solidwas recrystallized. Yields exceed 95%.

4.3.12. Diethyl 6,9-dihydro-6-oxo-2,4-diphenyl-4H-pyrimido[1,2-a]pyrimidine-3,7-dicarboxylate 8a. Mp(CH3CN): 241±2438C. IR (KBr): 3400±2400 (br), 1718,1708, 1664 cm21. 1H NMR (CDCl3): 0.9 (t, 3H, J�7 Hz,CH3), 1.4 (t, 3H, J�7 Hz, CH3), 3.9 (q, 2H, J�7 Hz, CH2),4.3 (q, 2H, J�7 Hz, CH2), 6.7 (s, 1H, H(8)), 7.0 (s, 1H,H(4)), 7.3±7.7 (m, 11H, Ar, and NH). 13C NMR (CDCl3):13.6, 14.5, 52.7, 60.6, 60.7, 104.3, 110.1, 127.7, 128.5,128.7, 128.9, 130.6, 133.2, 139.7, 145.2, 151.5, 156.5,157.8, 163.2, 163.6. Anal. Calcd for C25H23N3O5 (445.47):C, 67.41; H, 5.20; N, 9.43. Found: C, 67.04; H, 5.11; N,9.29.

4.3.13. Diethyl 6,9-dihydro-4-(4-methylphenyl)-6-oxo-2-phenyl-4H-pyrimido[1,2-a]pyrimidine-3,7-dicarboxyl-ate 8b. Mp (CH3CN): 255±2578C. IR (KBr): 3400±2500(br), 1720, 1705, 1665 cm21. 1H NMR (CDCl3): 0.9 (t, 3H,J�7 Hz, CH3), 1.4 (t, 3H, J�7 Hz, CH3), 2.3 (s, 3H, Ar±CH3), 3.9 (q, 2H, J�7 Hz, CH2), 4.3 (q, 2H, J�7 Hz, CH2),6.7 (s, 1H, H(8)), 7.0 (s, 1H, H(4)), 7.2±7.6 (m, 10H, Ar, andNH). 13C NMR (CDCl3): 13.6, 14.5, 21.2, 52.5, 60.6, 60.7,104.4, 110.0, 127.6, 128.5, 128.6, 129.5, 130.5, 133.2,136.9, 138.8, 145.0, 151.5, 156.5, 157.8, 163.2, 163.1.Anal. Calcd for C26H25N3O5 (459.50): C, 67.96; H, 5.48;N, 9.15. Found: C, 67.99; H, 5.28; N, 8.96.

4.3.14. Diethyl 6,9-dihydro-4-(4-methoxyphenyl)-6-oxo-2-phenyl-4H-pyrimido[1,2-a]pyrimidine-3,7-dicarboxyl-ate 8c. Mp (CH3CN): 253±2558C. IR (KBr): 3400±2400(br), 1715, 1708, 1664 cm21. 1H NMR (CDCl3): 0.9 (t,3H, J�7 Hz, CH3), 1.4 (t, 3H, J�7 Hz, CH3), 3.8 (s, 3H,OCH3), 3.9 (q, 2H, J�7 Hz, CH2), 4.3 (q, 2H, J�7 Hz,CH2), 6.7 (s, 1H, H(8)), 7.0 (s, 1H, H(4)), 6.9±7.7 (m,10H, Ar, and NH). 13C NMR (CDCl3): 13.6, 14.5, 52.3,55.3, 60.5, 104.4, 110.0, 114.2, 128.5, 128.7, 129.2, 130.5,131.9, 133.3, 144.9, 151.4, 156.5, 157.7, 159.9, 163.2,163.6. Anal. Calcd for C26H25N3O6 (475.50): C, 65.68; H,5.30; N, 8.84. Found: C, 65.55; H, 5.14; N, 8.66.

4.3.15. Diethyl 6,9-dihydro-4-(4-chlorophenyl)-6-oxo-2-phenyl-4H-pyrimido[1,2-a]pyrimidine-3,7-dicarboxyl-ate 8d. Mp (CH3CN): 263±2658C. IR (KBr): 3400±2450(br), 1715, 1708, 1664 cm21. 1H NMR (CDCl3): 0.9 (t, 3H,J�7 Hz, CH3), 1.3 (t, 3H, J�7 Hz, CH3), 3.9 (q, 2H,J�7 Hz, CH2), 4.3 (q, 2H, J�7 Hz, CH2), 6.7 (s, 1H,H(8)), 7.0 (s, 1H, H(4)), 7.2±7.6 (m, 10H, Ar, and NH).13C NMR (CDCl3): 13.6, 14.5, 52.4, 60.6, 103.9, 110.3,128.4, 128.7, 129.1, 129.2, 130.7, 133.1, 134.8, 138.3,145.3, 151.4, 156.2, 157.9, 163.1, 163.5. Anal. Calcd forC25H22ClN3O5 (479.92): C, 62.57; H, 4.62; N, 8.76.Found: C, 62.83; H, 4.64; N, 8.37.

J. J. Vanden Eynde et al. / Tetrahedron 57 (2001) 1785±1791 1791

4.3.16. Diethyl 6,9-dihydro-6-oxo-2-phenyl-4-(2-thienyl)-4H-pyrimido[1,2-a]pyrimidine-3,7-dicarboxylate 8e. Mp(EtOH): 225±2278C. IR (KBr): 3400±2400 (br), 1716,1703, 1665 cm21. 1H NMR (CDCl3): 0.9 (t, 3H, J�7 Hz,CH3), 1.4 (t, 3H, J�7 Hz, CH3), 3.9 (q, 2H, J�7 Hz, CH2),4.3 (q, 2H, J�7 Hz, CH2), 6.7 (s, 1H, H(8)), 7.3 (s, 1H,H(4)), 7.0±7.6 (m, 9H, Ph, thienyl, and NH). 13C NMR(CDCl3): 13.7, 14.5, 47.6, 60.8, 103.9, 110.1, 126.0,127.2, 127.4, 128.5, 128.7, 130.7, 133.0, 142.0, 145.8,151.0, 156.4, 157.8, 163.2, 163.3. Anal. Calcd forC23H21N3O5S (451.50): C, 61.19; H, 4.69; N, 9.31. Found:C, 61.15; H, 5.05; N, 9.27.

References

1. (a) Kappe, C. O. Tetrahedron 1993, 49, 6937±6963.

(b) Kappe, C. O. Acc. Chem. Res. 2000, in press.

2. (a) Cho, H.; Ueda, M.; Shima, K.; Mizuno, A.; Hayashimatsu,

M.; Ohnaka, Y.; Takeuchi, Y.; Hamaguchi, M.; Aisaka, K.;

Hidaka, T.; Kawai, M.; Takeda, M.; Ishihara, T.; Funahashi,

K.; Satoh, F.; Morita, M.; Noguchi, T. J. Med. Chem. 1989, 32,

2399±2406. (b) Atwal, K. S.; Rovnyak, G. C.; Schwartz, J.;

Moreland, S.; Hedberg, A.; Gougoutas, J. Z.; Malley, M. F.;

Floyd, D. M. J. Med. Chem. 1990, 33, 1510±1515. (c) Atwal,

K. S.; Rovnyak, G. C.; Kimball, S. D.; Floyd, D. M.;

Moreland, S.; Swanson, B. N.; Gougoutas, J. Z.; Schwartz,

J.; Smillie, K. M.; Malley, M. F. J. Med. Chem. 1990, 33,

2629±2635. (d) Atwal, K. S.; Swanson, B. N.; Unger, S. E.;

Floyd, D. M.; Moreland, S.; Hedberg, A.; O'Reilly, B. C.

J. Med. Chem. 1991, 34, 806±811.

3. (a) Bossert, F.; Meyer, H.; Wehinger, E. Angew. Chem. Int.

Ed. Engl. 1981, 20, 762±769. (b) Goldmann, S.; Stoltefuss, J.

Angew. Chem. Int. Ed. Engl. 1991, 30, 1559±1578.

4. (a) Wipf, P.; Cunningham, A. Tetrahedron Lett. 1995, 36,

7819±7822. (b) Kappe, C. O. Bioorg. Med. Chem. Lett.

2000, 10, 49±51.

5. (a) Kappe, C. O.; Kumar, D.; Varma, R. S. Synthesis 1999,

1799±1803. (b) Stadler, A.; Kappe, C. O. J. Chem. Soc.,

Perkin Trans. 2 2000, 1363±1368.

6. Snider, B. B.; Shi, Z. J. Org. Chem. 1993, 58, 3828±3839.

7. (a) Patil, A. D.; Kumar, N. V.; Kokke, W. C.; Bean, M. F.;

Freyer, A. J.; De Brosse, C.; Mai, S.; Truneh, A.; Faulkner,

D. J.; Carte, B.; Breen, A. L.; Hertzberg, R. P.; Johnson, R. K.;

Westley, J. W.; Potts, B. C. M. J. Org. Chem. 1995, 60, 1182±

1188. (b) Franklin, A. S.; Ly, S. K.; Mackin, G. H.; Overman,

L. E.; Shaka, A. J. J. Org. Chem. 1999, 64, 1512±1519.

(c) McDonald, A. I.; Overman, L. E. J. Org. Chem. 1999,

64, 1520±1528.

8. Milcent, R.; Malanda, J.-C.; Barbier, G.; Vaissermann, J.

J. Heterocycl. Chem. 1997, 34, 329±336.

9. (a) Ghosh, C. K.; Mukhopdhyay, K. K. J. Indian Chem. Soc.

1978, 55, 52±55. (b) Ghosh, C. K.; Mukhopdhyay, K. K.

J. Indian Chem. Soc. 1978, 55, 386±388. (c) Ito, K.;

Maruyama, J. J. Heterocycl. Chem. 1988, 25, 1681±1687.

(d) Sabitha, G. Aldrichim. Acta 1996, 29, 15±25.

10. Informations about microwave-mediated organic synthesis

may be found, i.e. on the following web sites:http://www-

ang.kfunigraz.ac.at/~kappeco; http://www.umh.ac.be/~orgafs.

11. Pouchert, C. J.; Behnke, J. The Aldrich library of 1H and 13C

FT NMR spectra; Aldrich Chemical: Milwaukee (MI, USA),

1992.

12. Altamore, A.; Cascarano, G.; Giacovazzo, C.; Virerbo, D.

Acta Crystallogr. 1991, A47, 744±748.

13. Straver, L.; Schierbeek, A. J.; MolEN. Structure determination

system. Nonius B.V. 1994.